CELLULAR PATHOPHYSIOLOGY OF ACUTE RENAL FAILURE

肾小管细胞损伤是急性肾衰综合征的重要组成部分。 继发于缺血和肾毒素的肾功能衰竭。过去的几个 多年来，在理解细胞病理生理学方面取得了进展。 这种伤害，但重大的根本性问题仍有待解决， 有可能减轻这种损伤的各种动作需要 澄清它们的效力和作用机制。这已经是 由于复杂的相互作用，体内研究极其困难 在完整的肾脏中发生的不受直接影响的因素 测量或实验操作。孤立的研究 亚细胞细胞器很有价值，但必须在外面完成。 它们实际发挥作用的综合细胞环境。这个 P.I.改进了一种悬浮液中分离的肾小管的制备方法， 富含近端片段，适合于关键的直接研究， 在良好控制的体外条件下，主要过程的 肾小管上皮细胞损伤的细胞病理生理学研究 腺嘌呤核苷酸代谢、细胞单价阳离子和钙离子 动态平衡，以及细胞脂质和磷脂代谢的变化。 模型中这些参数变化过程的初步研究 用该制剂建立的缺血性损伤的范围将延长 将开发研究肾病损伤的模型。初步 研究已经评估了一些药物的潜力，包括 磷脂酶抑制剂，钙离子通道阻滞剂，游离脂肪酸白蛋白， 不必要的溶质和外源腺嘌呤核苷酸的添加以改变 在该模型中的缺血性损伤的过程中发现显著的 对这些动作中的几个有好处。这些研究将是 扩展以更好地阐明哪些代理是有效和最佳的 使用它们的条件，并深入了解它们的机制 行动。其他拟议的研究将利用由 P.I.钙离子介导的线粒体膜损伤更好 探索在这个重要的细胞内位置的过程的本质。这个 因此，这项提案中的研究将为两者提供新的见解 肾小管细胞损伤的机制及丹参的疗效和作用机制 用于改善这种损伤的动作和相关的急性 肾功能衰竭。

Renal tubular cell injury is a critical component of the syndrome of acute renal failure secondary to ischemia and nephrotoxins. The past several years have seen progress in understanding the cellular pathophysiology of such injury but major fundamental issues remain to be resolved and a variety of maneuvers with potential for ameliorating such injury need to have their effiacy and mechanisms of action clarified. This has been extremely difficult with in vivo studies because of the complex interplay of factors occurring in the intact kidney which are not subject to direct measurement or experimental manipulation. Studies with isolated subcellular organelles have been valuable but are necessarily done outside of the integrated cellular milieu in which they actually function. The P.I. has refined a preparation of isolated renal tubules in suspension, enriched in proximal segments, which is suitable for critical direct study, under well controlled in vitro conditions, of major processes in the cellular pathophysiology of renal tubular cell injury including energy and adenine nucleotide metabolism, cellular monovalent cation and Ca++ homeostasis, and alterations in cell lipid and phospholipid metabolism. Preliminary studies on the course of changes in these parameters in a model of ischemic injury established with the preparation will be extended and models for study of nephrotic injury will be developed. Preliminary studies have evaluated the potential for a number of agents including phospholipase inhibitors, Ca++ channel blockers, fatty acid free albumin, impermeant solutes and exogenous adenine nucleotide addition to alter the course of ischemic injury in this model with the finding of significant beneficial effects for several of these maneuvers. These studies will be extended to better clarify which agents are effective and optimal conditions for their use and to gain insights into the mechanisms of their action. Additional proposed studies will utilize a model refined by the P.I. of Ca++ mediated injury to the inner mitochondrial membrane to better probe the nature of the process at this important intracellular site. The studies in this proposal will, thus, provide new insight into both mechanisms of renal tubular cell injury and efficacy and mechanisms of action of maneuvers for ameliorating such injury and the associated acute renal failure.